Continued Development of PARP Inhibitors Improves Outcomes for Patients With Ovarian Cancer
For many years, a diagnosis of ovarian cancerâ€”90% of which involve epithelial ovarian neoplasmsâ€”was a death sentence
For many years, a diagnosis of ovarian cancer—90% of which involve epithelial ovarian neoplasms—was a death sentence. Among the few effective treatments, particularly in the recurrent disease setting, unfavorable adverse effect (AE) profiles are barriers to care. At the Asembia Specialty Pharmacy Summit 2019, a panel discussed recent changes that have increased optimism.
Laura Alwan, PharmD, BCOP, and Jason Bergsbaken, PharmD, BCOP, covered this topic using case-based learning methods.
“Ovarian cancer is the fifth most common cause of cancer-related death for women in the United States,” Alwan said. “The average age at diagnosis is 63, and 70% of these patients present with advanced or metastatic disease. It’s critical to know that up to 25% of these patients have a somatic or germline BRCA mutation.”
The most promising development has been identification of the poly (ADP ribose) polymerase (PARP) inhibitors, small molecules that work at the cellular level to disrupt DNA repair and promote cell death in cancer cells. These drugs, although considered a breakthrough in their own right, work best when administered with other drugs. The cells that appear to be most sensitive to PARP inhibitors are those that have deficiencies in the homologous recombination DNA repair pathway, including patients with BRCA mutations or loss of heterozygosity.
Currently, the FDA has approved 3 PARP inhibitors specifically for ovarian cancer: olaparib, niraparib, and rucaparib. Olaparib was recently approved in the first-line maintenance setting for patients with BRCA mutations after complete or partial response to adjuvant platinumbased chemotherapy, making its indications slightly different from those of the other PARP inhibitors.
All 3 PARP inhibitors are approved as maintenance therapy in the recurrent disease setting, regardless of BRCA mutation status following at least a partial or complete response to platinum-based chemotherapy. Additionally, rucaparib and olaparib are approved as treatment for recurrent disease in patients with BRCA mutations who have received at least 2 or 3 prior lines of therapy, respectively.
After a review of clinical trial data that supported approval of this class of drugs, Alwan discussed toxicity, which generally occurs early in the first months of therapy but could happen anytime and usually resolves. Of note, anemia and thrombocytopenia tend to occur early. Nausea can be significant in the first 8 weeks but improve after the third or fourth cycles; fatigue, however, may be persistent. Clinicians should also watch for serum creatinine and liver enzyme elevations.
Resistance can be a problem with this class of drugs, generally occurring if homologous recombination deficiencies or BRCA mutations are restored. “Having PARP inhibitors available to treat ovarian cancer has led to significant improvements in progression-free survival,” Alwan said. “We don’t have good overall survival data yet, but, hopefully, we will soon.”
She also discussed companion diagnostics, tests that, to date, the FDA has approved for each specific agent and can identify BRCA mutations or other genetic markers of homologous recombination deficiencies. In the future, the FDA likely will approve these tests for drug classes rather than for an individual agent.
Bergsbaken covered how pharmacists can integrate PARP inhibitors into treatment and address specific payer and specialty pharmacy considerations. The National Institute for Occupational Safety and Health has proposed adding olaparib to its hazardous drug list, so it’s essential to counsel patients about storage, safe handling, and management of unused medications. In addition, patients need to know how to handle body secretions and waste at home.
Expanding on Alwan’s discussion of common AEs, Bergsbaken provided specific tips so pharmacists can counsel patients adequately. Many of his suggestions involved behavioral or lifestyle modifications that can be helpful.
Bergsbaken examined how oral chemotherapy requires comprehensive management. Its high cost, challenging distribution networks, and complicated regimens create access barriers and adherence challenges for patients. These drugs have AEs and are often involved in medication errors.
With the cost of cancer care increasing, it’s critical to monitor use of the newer antineoplastics and the management strategies used by payers and to be aware of the pros and cons of each. “A key question is how we define and standardize value, weighing outcomes and costs, given that value may be a moving target for patient-specific factors,” Bergsbaken said. Because of the conflicting evidence concerning cost-effectiveness, he looks forward having more robust information uncovered in the future.